- Exendin-4 (or Exenatide) is a medication currently used to treat diabetes, but it has shown promising results in tests of its effectiveness in protecting neurons from damaging processes associated with Alzheimer s disease. It is possible that Exendin-4 may be a treatment for Alzheimer s disease, which involves the gradual deterioration and death of neurons. Researchers are interested in studying the safety and comparing the effects of Exendin-4 with placebo to on congestive performance, overall clinical progression, various chemicals measured in blood and cerebrospinal fluid, and brain MRI, in individuals with early-stage Alzheimer's disease or mild cognitive impairment.

Objectives:

- To determine the safety and tolerability, as well as to acquire preliminary evidence for the effectiveness of twice daily administration of Exendin-4 as a treatment for early-stage Alzheimer s disease or mild cognitive impairment.

Eligibility:

- Individuals at least 60 years of age who have objective evidence of early-stage Alzheimer's disease or mild cognitive impairment in screening testing.

Design:

Participants will be screened.

Following the telephone screening, two in-person screening visits to determine eligibility.

The screening visit will involve a medical history and neurological examination, tests of memory and cognition, a lumbar puncture, collection of blood and saliva samples, and brain Magnetic Resonance Imagine (MRI) studies. Participants will be required to appoint a Durable Power of Attorney for research and medical care during this protocol.

Eligible participants will be divided into two groups. One group will receive Exendin-4, and the other will receive a placebo. Participants will keep a medication diary and will be scheduled for additional study visits 1 and 2 weeks after the start of the treatment.

Participants will have regular followup visits with blood tests, imaging studies, and other examinations 6, 12, and18 months after the start of the treatment. Another lumbar puncture may be performed optionally at the 18-month followup visit.

Detailed Description

Objective: Exendin-4 (or exenatide) is a medication currently used in the treatment of diabetes mellitus (DM). Exendin-4 has generated promising results as an agent protecting neurons from a number of assaults both in the laboratory and in studies on animals. Specifically, there is pre-clinical evidence that Exendin-4 may be a treatment for Alzheimer s disease (AD). Based on these facts, we propose a pilot Phase II double blind randomized placebo-controlled clinical study to assess the safety and provide proof of concept for efficacy of exendin-4 treatment in early Alzheimer s disease (AD), by demonstrating a response of disease biomarkers to the intervention. Our main hypothesis is that long-term administration of Exendin-4 in participants with amnestic MCI/early AD in FDA-approved doses is safe and will induce a change over time in AD biomarkers. Subject population: We intend to screen up to 100 potential participants in order to ensure that at least 40 participants (enrolled based on a clinical diagnosis of amnestic MCI/early AD and Cerebrospinal Fluid (CSF) biomarker evidence of AD) will be enrolled into treatment and complete the study. Design: Enrolled participants will be randomly assigned into one of two groups (Exendin-4 vs. Placebo) and will be followed at regular intervals for 18 months. Outcome measures: Safety and tolerability will be the primary outcomes. In addition, we will measure and assess the change over time of a number of exploratory outcomes with the intervention, including CSF and plasma biochemical biomarkers (such as CSF BDNF, A42, tau, p181-tau and plasma A42/A40), cognitive performance measures (such as the Alzheimer s Disease Assessment scale, cognitive sub-scale, and other tests), overall clinical progression measures (such as the Clinical Dementia Rating scale sum-of-boxes), volumetric changes on structural brain MRI and changes in default mode network activation on resting fMRI. All research will be performed on the National Institute on Aging (NIA) Clinical Research Unit located on the 5th floor of Harbor Hospital.

Medications stable for at least 4 weeks prior to screening. In particular:

Participants may take stable doses of antidepressants lacking significant anticholinergic side effects [if they are not currently depressed and do not have lifelong history of depression or history of major depression within the past 2 years or history of any episode of treatment-resistant depression (requiring > 1 antidepressants, Electrocunvulsive therapy etc)]

Cholinesterase inhibitors are allowable if started three months prior to enrollment

Adequate visual and auditory acuity to allow for neuropsychological testing

An informant or caregiver who has frequent contact with the participant (e.g. an average of 10 hours per week or more), must be available to provide history and accompany the participant to all clinic visits and ability to sign informed consent

Good general health with no additional disease states that could interfere with the study

Willing and able to complete all baseline assessments (including ApoE genotyping).

Willing to have an initial Lumbar Puncture and provide CSF at protocol specified time points

A history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities

Significant neuroimaging abnormalities, previously known or discovered on the initial MRI scan, including evidence of infection, infarction (> 3 mm in size) brain tumors (other than small meningiomas), or other focal lesions, multiple lacunes or lacunes in a critical memory structure or severe confluent microvascular disease (but not mild white matter changes, which are frequent with aging).

A positive RPR or HIV

Coagulopathy or anti-coagulant therapy (such as coumadin) increasing the risk for LP resulting in PT/PTT and INR within 1.5 standard deviation over the upper normal limit.

Investigators unable to obtain CSF at the clinical judgment of the investigator performing the procedure (failure of Lumbar Puncture after a limited number of unsuccessful attempts)

History of significant psychiatric disease, at the discretion of the Principal Investigator. Participants who develop psychiatric conditions necessitating treatment after their enrollment will not be dropped from the study. The high incidence of late-onset depression among individuals with MCI and AD requires that certain participants with depression, at the discretion of the Principal Investigator, should be included in the cohort to maintain the ecological validity of the results.

Significant history of alcoholism or substance abuse (at the judgment of the investigator).

Known diagnosis of diabetes at the time of enrollment or new diagnosis diabetes based on the findings of elevated fasting blood glucose (greater than or equal to 126 mg/dL) and/or the oral glucose tolerance test at screening (> 200 mg/dl at two hours).

Severe renal impairment (creatinine clearance < 30 ml/min) or end-stage renal disease. Individuals with moderate renal impairment (creatinine clearance 30 to 50 ml/min) may be enrolled in the study, but their BUN and Creatinine will be followed closely. All participants, in whom BUN or creatinine increased after switching from 5 microg SC bid to 10 microg SC bid (but not with 5 microg SC bid), will be switched back to 5 microg SC bid. If the BUN/Creatinine elevation persists one week later with the lower dose, the participant will be withdrawn from the study.

Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2.

Current or previous treatment with Exendin-4

AD or MCI participants who started cholinesterase inhibitor treatment less than three months ago. These participants may be enrolled after three months of initiation of treatment. Participants with AD may not be treated with memantine at the time of enrollment (since this treatment is approved for moderate AD), but may subsequently be placed on it, at the discretion of their treating physicians.

History of pancreatitis, active upper GI, hepatic or gallbladder disease

History of repeated hypoglycemia

Body mass index (BMI) < 20 on enrollment (given the expected weight loss caused by Exendin-4 and dementia). In the BLSA, participants with age > 65 had a mean BMI of 25.8 with SD of 3.9. Exendin-4 has been shown to cause an average 5.3 kg weight loss, with 95% CI: 6 to 4.5 kg.

Allergy to Exendin-4 or to substances in the injection pen (metacresol, mannitol, glacial acetic acid, sodium acetate trihydrate, water for injection)

Participation in other studies of investigational treatments for Alzheimer s disease